Search PubMed⌕ Search

Biomedical subjects

R J Smith

Publications and source records attributed to R J Smith.

At least 163 records · Page 9Linked to original sources
PubMed1998

Passage to India: the search for genes causing autosomal recessive nonsyndromic hearing loss.

Hereditary hearing impairment affects approximately 0.05% of all children born in the United States. It is most commonly autosomal recessive, nonsyndromic, and monogenic [autosomal recessive nonsyndromic hearing loss (ARNSHL)]. Although the number of disease loci is not known, some estimates exceed 100. Using a strategy of homozygosity mapping to localize ARNSHL genes by screening consanguineous families for chromosomal regions that are homozygous by descent, we have mapped several genes in multiplex, nuclear, consanguineous families in Tamil Nadu, India. From the mean frequency of the ARNSHL genes in this population, the total number of disease genes is estimated to be 57.

Chromosome Mapping↗
PubMed1998

Treatment of topographic central islands following refractive surgery.

PURPOSE: To evaluate the safety and efficacy of using central reablation to treat topographic central islands following photorefractive keratectomy (PRK), myopic keratomileusis in situ, and laser in situ keratomileusis (LASIK). SETTING: Department of Ophthalmology, Stanford University School of Medicine, Stanford, and Jules Stein Eye Institute, Los Angeles, California, USA. METHODS: Central reablation was performed on eight eyes with clinically significant topographic central islands after refractive surgery. Two eyes developed central islands after PRK, five eyes after LASIK, and one eye after myopic keratomileusis in situ. A clinically significant topographic central island was defined as an area of steepening of at least 3.0 diopters by at least 1.5 mm in diameter documented by computerized videokeratography. Reablation was tailored to each eye based on the diameter and power of the topographic central island using the Munnerlyn formula. RESULTS: All eyes experienced a reduction or elimination of the topographic central islands following central reablation. Six eyes experienced an improvement in uncorrected visual acuity, and all eyes returned to within one line of their preoperative level of best spectacle-corrected visual acuity 1 month after the procedure. CONCLUSION: Topographic central islands following PRK, myopic keratomileusis in situ, and LASIK can be effectively treated using the excimer laser. Poor predictability of the refractive effect of central reablation may be the limitation of this treatment modality.

Adult↗
PubMed1998

Frontotemporal cerebral blood flow change during executive and declarative memory tasks in schizophrenia: a positron emission tomography study.

Schizophrenia affects prefrontal and temporal-limbic networks. These regions were examined by contrasting regional cerebral blood flow (rCBF) during executive (Wisconsin Card Sorting Test [WCST]), and declarative memory tasks (Paired Associate Recognition Test [PART]). The tasks, and a resting baseline, were administered to 15 patients with schizophrenia and 15 healthy controls during 10 min positron emission tomography 15O-water measures of rCBF. Patients were worse on both tasks. Controls activated inferior frontal, occipitotemporal, and temporal pole regions for both tasks. Similar results were obtained for controls matched to level of patient performance. Patients showed no activation of hypothesized regions during the WCST and activated the dorsolateral prefrontal cortex during the PART. On the PART, occipitotemporal activation correlated with better performance for controls only. Better WCST performance correlated with CBF increase in prefrontal regions for controls and in the parahippocampal gyrus for patients. Results suggest that schizophrenia may involve a breakdown in the integration of a frontotemporal network that is responsive to executive and declarative memory demands in healthy individuals.

Adult↗
PubMed1998

Nonsyndromic hearing impairment is associated with a mutation in DFNA5.

Nonsyndromic hearing impairment is one of the most heterogeneous hereditary conditions, with more than 40 loci mapped on the human genome, however, only a limited number of genes implicated in hearing loss have been identified. We previously reported linkage to chromosome 7p15 for autosomal dominant hearing impairment segregating in an extended Dutch family (DFNA5). Here, we report a further refinement of the DFNA5 candidate region and the isolation of a gene from this region that is expressed in the cochlea. In intron 7 of this gene, we identified an insertion/deletion mutation that does not affect intron-exon boundaries, but deletes five G-triplets at the 3' end of the intron. The mutation co-segregated with deafness in the family and causes skipping of exon 8, resulting in premature termination of the open reading frame. As no physiological function could be assigned, the gene was designated DFNA5.

Adolescent↗
PubMed1998

Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment.

The tectorial membrane is an extracellular matrix of the inner ear that contacts the stereocilia bundles of specialized sensory hair cells. Sound induces movement of these hair cells relative to the tectorial membrane, deflects the stereocilia, and leads to fluctuations in hair-cell membrane potential, transducing sound into electrical signals. Alpha-tectorin is one of the major non-collagenous components of the tectorial membrane. Recently, the gene encoding mouse alpha-tectorin (Tecta) was mapped to a region of mouse chromosome 9, which shows evolutionary conservation with human chromosome 11q (ref. 3), where linkage was found in two families, one Belgian (DFNA12; ref. 4) and the other, Austrian (DFNA8; unpublished data), with autosomal dominant non-syndromic hearing impairment. We determined the complete sequence and the intron-exon structure of the human TECTA gene. In both families, mutation analysis revealed missense mutations which replace conserved amino-acid residues within the zona pellucida domain of TECTA. These findings indicate that mutations in TECTA are responsible for hearing impairment in these families, and implicate a new type of protein in the pathogenesis of hearing impairment.

Alternative Splicing↗
PubMed1998

Localization of a gene for otosclerosis to chromosome 15q25-q26.

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi-generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease-causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.

Adult↗
PubMed1998

Two frequent missense mutations in Pendred syndrome.

Pendred syndrome is an autosomal recessive disorder characterized by early childhood deafness and goiter. A century after its recognition as a syndrome by Vaughan Pendred, the disease gene ( PDS ) was mapped to chromosome 7q22-q31.1 and, recently, found to encode a putative sulfate transporter. We performed mutation analysis of the PDS gene in patients from 14 Pendred families originating from seven countries and identified all mutations. The mutations include three single base deletions, one splice site mutation and 10 missense mutations. One missense mutation (L236P) was found in a homozygous state in two consanguineous families and in a heterozygous state in five additional non-consanguineous families. Another missense mutation (T416P) was found in a homozygous state in one family and in a heterozygous state in four families. Pendred patients in three non-consanguineous families were shown to be compound heterozygotes for L236P and T416P. In total, one or both of these mutations were found in nine of the 14 families analyzed. The identification of two frequent PDS mutations will facilitate the molecular diagnosis of Pendred syndrome.

Adolescent↗
PubMed1998

A PCR technique based on the Hip1 interspersed repetitive sequence distinguishes cyanobacterial species and strains.

The use of primers based on the Hip1 sequence as a typing technique for cyanobacteria has been investigated. The discovery of short repetitive sequence structures in bacterial DNA during the last decade has led to the development of PCR-based methods for typing, i.e., distinguishing and identifying, bacterial species and strains. An octameric palindromic sequence known as Hip1 has been shown to be present in the chromosomal DNA of many species of cyanobacteria as a highly repetitious interspersed sequence. PCR primers were constructed that extended the Hip1 sequence at the 3' end by two bases. Five of the 16 possible extended primers were tested. Each of the five primers produced a different set of products when used to prime PCR from cyanobacterial genomic DNA. Each primer produced a distinct set of products for each of the 15 cyanobacterial species tested. The ability of Hip1-based PCR to resolve taxonomic differences was assessed by analysis of independent isolates of Anabaena flos-aquae and Nostoc ellipsosporum obtained from the CCAP (Culture Collection of Algae and Protozoa, IFE, Cumbria, UK). A PCR-based RFLP analysis of products amplified from the 23S-16S rDNA intergenic region was used to characterize the isolates and to compare with the Hip1 typing data. The RFLP and Hip1 typing yielded similar results and both techniques were able to distinguish different strains. On the basis of these results it is suggested that the Hip1 PCR technique may assist in distinguishing cyanobacterial species and strains.

Bacterial Proteins↗
PubMed1998

Contig maps and genomic sequencing identify candidate genes in the usher 1C locus.

Usher syndrome 1C (USH1C) is a congenital condition manifesting profound hearing loss, the absence of vestibular function, and eventual retinal degeneration. The USH1C locus has been mapped genetically to a 2- to 3-cM interval in 11p14-15.1 between D11S899 and D11S861. In an effort to identify the USH1C disease gene we have isolated the region between these markers in yeast artificial chromosomes (YACs) using a combination of STS content mapping and Alu-PCR hybridization. The YAC contig is approximately 3.5 Mb and has located several other loci within this interval, resulting in the order CEN-LDHA-SAA1-TPH-D11S1310-(D11S1888/KCNC1 )-MYOD1-D11S902D11S921-D11S 1890-TEL. Subsequent haplotyping and homozygosity analysis refined the location of the disease gene to a 400-kb interval between D11S902 and D11S1890 with all affected individuals being homozygous for the internal marker D11S921. To facilitate gene identification, the critical region has been converted into P1 artificial chromosome (PAC) clones using sequence-tagged sites (STSs) mapped to the YAC contig, Alu-PCR products generated from the YACs, and PAC end probes. A contig of >50 PAC clones has been assembled between D11S1310 and D11S1890, confirming the order of markers used in haplotyping. Three PAC clones representing nearly two-thirds of the USH1C critical region have been sequenced. PowerBLAST analysis identified six clusters of expressed sequence tags (ESTs), two known genes (BIR, SUR1) mapped previously to this region, and a previously characterized but unmapped gene NEFA (DNA binding/EF hand/acidic amino-acid-rich). GRAIL analysis identified 11 CpG islands and 73 exons of excellent quality. These data allowed the construction of a transcription map for the USH1C critical region, consisting of three known genes and six or more novel transcripts. Based on their map location, these loci represent candidate disease loci for USH1C. The NEFA gene was assessed as the USH1C locus by the sequencing of an amplified NEFA cDNA from an USH1C patient; however, no mutations were detected.

Bacteriophage P1↗
PubMed1998

At risk in two worlds: injury mortality among indigenous people in the US and Australia, 1990-92.

This paper outlines the commonalties and unique differences in injury experience among the indigenous people in the United States and Australia. Injury mortality rates among Indigenous people in the United States and Australia are approximately 2-3 times greater than rates for the non-Indigenous population in each country. Motor vehicle-related injuries accounted for one-third of the injury deaths for Native Americans and Australian Aboriginals. Suicide accounted for more deaths in Native Americans (15.5 per 100,000) than it did for Australian Aboriginals (11.1 per 100,000), whereas the injury death rate in Australian Aboriginals due to poisoning was almost twice that of Native Americans. Culturally appropriate interventions tailored to specific local settings and problems will be necessary to reduce injury mortality among Indigenous people.

Accidents, Traffic↗
PubMed1998

A Moroccan family with autosomal recessive sensorineural hearing loss caused by a mutation in the gap junction protein gene connexin 26 (GJB2).

We report a mutation in the connexin 26 gene (Cx26) in a consanguineous Moroccan family linked to the DFNA3/DFNB1 locus on human chromosome 13q11-q12. Affected subjects display congenital, bilateral, sensorineural hearing loss. We have previously identified Cx26 mutations in consanguineous Pakistani families. This current finding indicates that Cx26 mutations are not restricted to ethnically and geographically distinct populations. This is an important observation since it will help to determine the overall contribution of connexin 26 mutations to autosomal deafness in different populations.

Child, Preschool↗
PubMed1998

Role of substance P in the laryngeal chemoreflex.

The laryngeal chemoreflex (LCR) is a potentially life-threatening reflex that is elicited in immature animals by the topical application of water to the laryngeal mucosa. The reflex response is characterized by immediate apnea and laryngeal adduction and delayed cardiovascular instability. The cardiorespiratory changes of the LCR may be life-threatening, particularly in very immature animals such as piglets under 2 weeks of age. The afferent and efferent limbs of the LCR are mediated through the vagus nerve, but the neuromediators responsible for the reflex changes have not yet been clearly elucidated. Previous agonist and antagonist studies in immature dogs demonstrated that substance P, a sensory tachykinin, mediates the life-threatening esophagolaryngeal adductor reflex elicited by distal esophageal sensory nerve stimulation. This study was conducted to determine if substance P also plays a role in mediating the LCR. The LCR response was compared before and after treatment with intravenous substance P antagonist (Pfizer CP-96,345-1) in eight piglets (mean 27.7 days of age). The laryngeal and cardiovascular responses of the animals following intravenous administration of the tachykinins substance P, neurokinin A, and neurokinin B were also assessed. Pretreatment with substance P antagonist did not alter the LCR's duration of apnea (p > .10), laryngeal adductor response, or early change in mean arterial pressure (p > .10), although the early maximal heart rate response was significantly altered (p < .01). Intravenous substance P, neurokinin A, and neurokinin B did not reproduce the laryngeal respiratory response of the LCR. We conclude that substance P, neurokinin A, and neurokinin B are not key neurotransmitters of the LCR.

Animals↗
PubMed1998

External rhinoplasty approach for extirpation and immediate reconstruction of congenital midline nasal dermoids.

Surgical extirpation is the treatment of choice for nasal dermoids in the pediatric population. Approaches include vertical-dorsal rhinotomy, lateral rhinotomy, transverse rhinotomy, and external rhinoplasty. While short-term results suggest that the last approach is cosmetically most acceptable, the required wide undermining of the nasal tip and dorsum may affect subsequent nasal growth. To assess long-term results, we reviewed our experience with 8 cases encountered over the past 10 years. Modifications of the technique to minimize midline dorsal depression are described.

Adolescent↗
PubMed1998

Leptin signaling in the hypothalamus of normal rats in vivo.

Leptin has been shown to activate multiple signaling molecules in cultured cells, including Janus kinase-2, STAT (signal transducer and activator of transcription) proteins, and mitogen-activated protein kinase, and to stimulate the DNA-binding activity of STAT3 in mouse hypothalamus. In this study, the activation of candidate leptin signaling molecules in the hypothalamus of normal rats in vivo was investigated. Fasted male Sprague-Dawley rats were injected iv with recombinant murine leptin or vehicle. Plasma leptin concentrations were determined at defined time points, and the phosphorylation of signaling proteins was assessed in hypothalamic lysates. There was a marked increase in plasma leptin concentration at 2 min and a gradual decline by 45 min after leptin injection. Immunoblotting analysis of hypothalamic lysates with a phosphospecific STAT3 antibody demonstrated a time-dependent stimulation of STAT3 tyrosine phosphorylation. STAT3 phosphorylation was first evident at 5 min and was maximal at 30 min after leptin injection. By contrast, leptin did not increase the phosphorylation of Janus kinase proteins, mitogen-activated protein kinase, or STAT1 and -5 despite abundant expression of these signaling molecules in the hypothalamus. These results differ from findings in cultured cells and in vitro systems. It remains unclear how signaling is propagated downstream from the leptin receptor to STAT3, but this may involve novel signaling intermediates.

Animals↗
PubMed1998

Intestinal adaptation after extensive small bowel resection: differential changes in growth and insulin-like growth factor system messenger ribonucleic acids in jejunum and ileum.

The distal small bowel exhibits greater adaptive growth than proximal segments after partial small intestine resection. To explore this process, we evaluated adaptive cellularity, intestinal insulin-like growth factor (IGF) system messenger RNA (mRNA) transcripts, and effects of recombinant IGF-I treatment in jejunum and ileum of adult rats. Gastrostomy-fed animals underwent 80% jejuno-ileal resection or intestinal transection and reanastomosis without resection, followed by infusion of human recombinant IGF-I (2.4 mg/kgXday) or vehicle. After 7 days, resected rats demonstrated modest adaptive growth in jejunum and marked cell proliferation in ileum. Resection increased IGF-I mRNA in both jejunum (183%) and ileum (249%) and up-regulated IGFBP-4 mRNA levels in both tissues. IGFBP-3 mRNA fell significantly in ileum after resection. IGF-I infusion modestly increased ileal cellularity after resection, but had no effect in jejunum. IGF-I markedly increased IGFBP-3 mRNA levels in jejunum after both transection and resection. These data confirm that bowel resection induces greater adaptive growth in ileum than jejunum. IGF-I administration modestly increases ileal, but not jejunal, growth after resection. Increased levels of intestinal IGF-I and IGFBP-4 mRNA suggest roles for IGF-I and IGFBP-4 in mediating small bowel adaptation. Higher levels of jejunal IGFBP-3 mRNA may be related to limited jejunal vs. ileal growth after extensive jejuno-ileal resection.

Adaptation, Physiological↗
PubMed1998

Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography.

BACKGROUND: The diagnosis of malignant mesothelioma is a challenging medical problem. CT often cannot differentiate between benign diffuse pleural thickening and malignant mesothelioma, while thoracentesis and CT-guided biopsies are insensitive. We have assessed the value of positron emission tomography (PET) with 2-fluoro-2-deoxy-D-glucose (FDG) in the evaluation of malignant mesothelioma. METHODS: Twenty-eight consecutive patients referred for the evaluation of suspected malignant mesothelioma were evaluated by FDG-PET imaging. Measured attenuation correction was performed in 26 of 28 cases for quantitation with the standardized uptake value (SUV) method. The results of PET imaging were compared with those of video-assisted thoracoscopy or surgical biopsies. RESULTS: Surgical biopsy specimens confirmed the presence of malignant disease in 24 patients and demonstrated benign processes in the remaining four. The uptake of FDG was significantly higher in malignant than in benign lesions (SUV=4.9+/-2.9 and SUV=1.4+/-0.6, respectively; p<0.0001). With a SUV cutoff of 2.0 to differentiate between malignant and benign disease, a sensitivity of 91% and a specificity of 100% could be achieved, although the activity in some epithelial mesotheliomas tended to be close to this threshold. FDG-PET images provided excellent delineation of the active tumor sites. Hypermetabolic lymph node involvement was noted on FDG-PET images in 12 patients, 9 of which appeared normal on CT scans. Histologic examination in six patients confirmed malignant nodal disease in five cases and indicated granulomatous lymphadenitis in one. CONCLUSION: In this highly selected population, FDG-PET imaging was a sensitive method to identify malignant mesothelioma and determine the extent of the disease process.

Biopsy↗
PubMed1997

Potentiation of apoptosis by low dose stress stimuli in cells expressing activated MEK kinase 1.

MEK kinases (MEKKs) are serine-threonine kinases that regulate sequential protein phosphorylation pathways involving mitogen-activated protein kinases (MAPKs), including members of the Jun kinase (JNK) family. MEKK1 is a 196 kDa protein that when cleaved by caspase-3-like proteases generates an active COOH-terminal kinase domain. Expression of the MEKK1 kinase domain is sufficient to induce apoptosis. Mutation of MEKK1 to prevent its proteolytic cleavage protects cells from MEKK1-mediated cell death even though the JNK pathway is still activated, indicating that JNK activation is not sufficient to induce cell death. The inducible acute expression at modest levels of the activated MEKK1 kinase domain can be used to potentiate the apoptotic response to low dose ultraviolet irradiation and cisplatin. Similarly, in L929 fibrosarcoma cells inducible acute expression of the kinase domain of MEKK1 markedly increased the cell death response to tumor necrosis factor alpha (TNF alpha). The findings demonstrate that acute expression of an active form of MEKK1 can potentiate the cell death response to external stress stimuli. Manipulation of MEKK1 proteolysis and its regulation of signal pathways involved in apoptosis has significant potential for anticancer therapies when used in combination with therapeutic agents at doses that alone have little or modest effects on cell viability.

3T3 Cells↗